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H1N1 Influenza Virus: Immune Responses During Pregnancy

The human respiratory infection caused by the influenza virus strain H1N1—popularly known as swine flu—was first recognized in the spring of 2009. A few months after the first swine flu cases were reported, rates of confirmed H1N1-related illness increased in much of the world. As a result, the World Health Organization declared the infection a global pandemic. However, the pandemic was declared over in August 2010. Currently, H1N1 is still circulating in humans as a seasonal flu virus, and it is included in the current seasonal flu vaccine (2016-2017). One of the groups at increased risk of infection is pregnant mothers.

During pregnancy, a mother’s immune system is suppressed to protect the fetus, which is perceived as a foreign body because it is genetically different. It is not surprising, then, that pregnant women are at increased risk of developing infection with influenza and, once infected, are more likely to develop severe disease. A 2010 World Health Organization analysis of the 2009 H1N1 influenza pandemic found that pregnant women were 7 times more likely to be hospitalized and twice as likely to die from H1N1 infection than non-pregnant women. Now, results from a new study highlight potential mechanisms at the basis of the increased susceptibility of pregnant women to H1N1 infection. The study (Pregnancy-Related Immune Adaptation Promotes the Emergence of Highly Virulent H1N1 Influenza Virus Strains in Allogenically Pregnant Mice) published on March 8, 2017, shows that, in pregnant mice, the H1N1 influenza virus causes more severe infections and mutates into a more virulent strain in only a few days.

Gülsah Gabriel, co-lead author of the study, said in a press release: “The first line of defense of the immune system, the innate immune response, is not acting quickly enough to clear the virus. The virus takes advantage of this permissive environment and mutates very fast. This is what influenza viruses do best. The new variants are responsible for increased virulence.”

For the study, researchers used a mouse model that mimics human pregnancy. Previous influenza studies in mice evaluated syngenic pregnancies—mice were pregnant with genetically identical fetuses. However, these pregnancies do not mimic natural human pregnancies, which are allogenic—babies are the product of the combined genes of a mother and father. Thus, in allogenic pregnancies, the fetuses differ genetically from the mother. The researchers found that the immune system is more suppressed in allogenic pregnancies than in syngenic pregnancies.

To understand immune suppression in mice with allogenic (genetically distinct pregnancies), the researchers examined gene expression patterns in immune cells during infection. They found that the genes responsible for releasing cytokines such as type 1 interferon were suppressed, resulting in a weak initial response to infection. In addition, genes responsible for activating and recruiting cytotoxic T cells to the site of infection—the lungs—were suppressed, resulting in impaired migration of these cells to the lungs, where they directly attack the virus.

The researchers also found that virus variants that specifically counteract type I interferon response and mediate increased viral pathogenicity appeared quickly following infection in pregnant mice, but not in non-pregnant mice.

The study results underscore the importance of influenza vaccination compliance in pregnant women.

24 comments

The results of the study included in this blog post are alarming. The fact that H1N1 can mutate faster and have increased virulence in pregnant mothers is scary. The study presented above emphasizes the importance for pregnant women to be vaccinated against influenza. A recent study lends more support for influenza vaccination during pregnancy. The researchers found that women who received the influenza vaccine during pregnancy had the best seropositivity compared to women who were vaccinated before conception or not vaccinated at all (1). This type of information needs to be relayed to pregnant women so that the mother and her child can be protected. I think that if more women understood the risk in not being vaccinated against influenza, then they would choose to get the vaccine.

Megan,
I agree completely with your reasoning. The fact that pathogens such as the H1N1 influenza strain can have a stronger effect on pregnant mothers than on the general population is a thought-provoking matter to consider. Vaccinations for pregnant women are oftentimes essential in preventing the fetus from obtaining a disease and for the passing of maternal antibodies across the placenta to the fetus. For example, whooping cough (pertussis) is a serious disease that leads to serious coughing spells and can be deadly in infants. It is advised that pregnant women receive the whooping cough vaccine (Tdap) as that will create maternal antibodies that will be passed on to the fetus thus preventing the fetus from obtaining whooping cough. A study found that the whooping cough booster is highly protective for newborns and it is recommended for pregnant women who have not taken the booster to do so (1).

I completely agree with you that more women should understand the risks of not being vaccinated. In fact, a study done on pregnant Saudi Arabia women has shown how many are actually not vaccinated. About thirteen percent of the 1000 patients were poorly aware of the safety and benefits of the influenza vaccine (1). The women believed that the vaccine was not safe for their pregnancy and were rarely offered to be vaccinated by their doctors (1). Not only is this a potential risk to many women in Saudi Arabia, it is also threatening to many pregnant women around the world. Lacking knowledge on the benefit of vaccination against infectious diseases could have long term effects on women and their babies.

That is very true that this information needs to be to relayed to pregnant women but one thing that keeps arising around vaccination and pregnancy is the fear of agents or preservatives present in vaccines that may “cause” autism or any other neurological/behavioral diseases in the born child.

I agree, the information presented were very alarming, but I’m glad there are studies like this out for the public knowledge. Pregnant women need to be aware of the risks they are taking when they make a choice not to be vaccinated. In order to fully understand how great of a risk pregnant women are in, more studies will have to be conducted and with allogenic fetus case. Overall this study was interested as it revealed a risk in how mother nature works towards pregnant women.

The findings of this study were very interesting to me. I always knew that pregnant mothers were typically given closer looks when deciding medications to prescribe but I really did not know about the increased virulence of pathogens such as the H1N1 Influenza virus in pregnant individuals. It is also interesting knowing that the mother’s immune system has to be suppressed in a sense as the presence of a foreign being (the fetus) is within the mother and the immune system must be prevented from attacking the fetus.To avoid the problem of getting a sickness like this in the first place, it is recommended that pregnant mothers receive flu vaccinations to prevent the dangerous of being sick while pregnant; pregnant women who received the influenza vaccine had a decreased risk of having preterm and low birth weight babies (1).
I am also extremely interested in the science behind transplant medicine as similar issues exist in transplant recipients who must have an organ match so that the body’s immune system does not attack and destroy the foreign donated organ; immunosuppressive drugs are given to transplant recipients in order to ensure that their immune system does not attack the donated organ in a similar way to a mother’s immune system works to avoid attacking the fetus.

Immunosuppression is common in pregnant women, and virulence factors in pathogens increase as a result. During the cold winter months, influenza is at its peak and complications in a pregnant woman can be severely life threatening. So I am a strong supporter of your idea of expecting mothers (and all individuals) becoming vaccinated yearly against new influenza serotypes. When a vaccine is given, the weakened pathogen or its immunogens are detected by lymphocytes of the immune system. B-lymphocytes differentiate into plasma cells and release antibodies to neutralize the invading immunogen while helper T-lymphocytes and cytotoxic T-lymphocytes work in tandem to destroy the remnants of the immunogen. Memory B-lymphocytes and T-lymphocytes stimulate immunological memory in the body so that if the same immunogen is ever encountered in the future, a secondary immune response is rapidly produced that kills the pathogen before infection can occur. Oseltamivir (Tamiflu) is an antiviral drug, and along with other compounds such as L-NMMA, that can treat patients infected with influenza, but it has a critical period in which the drug must be taken around the first five days of infection to be effective, making it unreliable in some situations (1). And plus, it is better to prevent a problem from occurring rather than treating it down the road.

Thomas, it looks like you have asked an important question there that I have actually addressed in my comment. There exist ways to help women who go through repetitive miscarriages using allogenic leukocytes from the father’s or husbands to decrease the chance of miscarriages. So when the man’s cells are introduced or presented to the woman’s immune system, the woman gets accustomed to the husbands cells and less antibodies are made against the fetus which is considered as the pathogen leading to successful pregnancies. I could not find full articles but check this (1) https://www.ncbi.nlm.nih.gov/pubmed/15915992

Pregnant women are more susceptible to severe symptoms caused by viral infections, suggesting the importance of influenza vaccination of pregnant women. However, many people still worry about the safety of vaccination and are afraid of any adverse influence of maternal vaccination on children. Those worries may not be necessary. A recent study investigated the pandemic influenza A (H1N1) vaccination in pregnancy and its relationship between early childhood morbidity in offspring (1). This study involved mothers who were unexposed to vaccine and mothers who were vaccinated in different trimesters of pregnancy. No increased risk for early childhood morbidity was found based on the analysis of more than 60000 children. Moreover, infants may obtain immunity from maternal vaccination. According to a study, maternal vaccination can effectively prevent infant pertussis (2). The newborns whose mother received the combined tetanus, diphtheria and acellular pertussis (Tdap) vaccine had more antibodies at birth and during the first two months of life. Another study also shows that compared to postpartum vaccination, Tdap vaccination at 27-36 weeks gestation was 85% more effective at preventing pertussis in infants less than two months of age (3). Maternal vaccination not only helps maintain mothers` health but also provides protection for newborns. In my opinion, maternal vaccination is a wise choice.

Great point Lanqiao! I agree that the influenza vaccine has significantly evolved since it was first discovered. At the beginning of its use, this vaccine would have side effects such as fever and myalgias (1). Now, through various studies, the influenza vaccine has been proven to cause very few adverse side effects. The overall frequency of symptoms in pregnant women is very low as found in one study that analyzed women administered the vaccine and women without it (2). Not only does the flu shot aid in the points you covered but it helps in even more ways! It decreases the risk for pre-term births, reduces neonatal morbidity, and decreases the chances of an infant being smaller than its gestational age (3).

I agree with Lanqiao. Maternal vaccination is a vital aspect of reducing H1N1 infection in new born children. Some people worry about the detrimental effects of vaccines. The section from article one gives sufficient evidence regarding the difference in vaccinated and non-vaccinated childhood morbidity. The main article states that pregnant women are much more likely to die via H1V1 influenza. This then made think about the specific factors that are affecting maternal immune tolerance of pathogens. In one study, regulatory T cells are determined to have the primary role in maintain immunological tolerance in the mothers. (1) This leads me to believe that the T cell receptors do not work as well in pregnant women.

The ability of H1N1 to mutate in very fast rates and produce more dangerous strains in pregnant women is really mind blowing. Pregnant women protection is major concern and H1N1 vaccination plays an important role in that. Vaccinated women have a higher chance of raising a heather child. According to a study that published in August 2014, pups of influenza vaccinated mothers were less likely to be infected by influenza during their early lives. The protection of the pups was due to the anti-influenza antibodies transfer from the mothers to the pups via breast feeding (1). Therefore, educating people and especially women of the importance of vaccination and breast feeding to the child and the mother should be a major concern in the upcoming years.
1) https://www.ncbi.nlm.nih.gov/pubmed/24958701

Pregnancy is a critical time for both mother and child and what happens during this period affects rest of the life. This finding is not surprising because during pregnancy human body is very vulnerable due to suppressed immune system and risk by any infections are elevated. It is a well-established fact that virus like Zika which clears itself in few days in any healthy person produce microcephaly in the child if the mother is infected during pregnancy (1). In another study, children born from the mother with the flu during pregnancy were found to be seven times more likely to get schizophrenia as adults. It was found that chemical mediators of inflammation in infected mothers, such as interleukin- 1β, interleukin-6 and tumor necrosis factor-α directly affects the development of fetal brain increasing the risk of schizophrenia later in life (2). It is shocking how small complications during pregnancy can significantly compromise child’s health. A little neglect of not getting a flu shot by a mother can cost unborn children their health. Studies like these highlights the importance and necessity of educating public about vaccination.

I couldn’t agree with you more, Prakash. It seems that everything that could go wrong in an infectious disease does so when it comes to pregnant mothers. As you mentioned, Zika leads not only to microcephaly in the child but also could be associated with hydrops fetalis, hydranencephaly, and fetal demise (1). I would like to add that a woman infected with influenza, will not only be affected during pregnancy. Their symptomology can continue to adversely affect their child during the breastfeeding period as well (2). This model was studied in ferrets, and it was shown that live H1N1 influenza viruses could be found in the mammary glands and milk of the breastfeeding mothers (2). Eventually, these mothers stopped producing milk altogether (2). This is a serious problem for a developing baby, which relies on breast milk for its acquired immunity (2). Once again, I reiterate the importance of vaccinations against these infections to prevent fetal and infant infections and mortality.

This blog post brought some great points on the importance of pregnant women getting vaccinated for Influenza. Influenza can cross the placenta and cause some severe birth defects. In a study, Tabynov and his colleagues showed that a vaccine containing Brucella proteins Omp 16 and L7/L12 improved T-cell immune response and provided significant protections in pregnant Heifers.Clearly, maternal vaccination is a wise choice, but not every mother will accept the vaccine. People still think getting vaccines cause their child to develop Autism. Even though it is not true, people still believe in that miss conception about vaccines. Other factors like religion, poverty and culture beliefs keep pregnant mothers from getting Influenza shots.It not only important to vaccinate pregnant women, it is also important to educate people why it is important and clear out all the misconception

It is interesting that although a fetus is part of the mother’s body, her immune system has to be suppressed in order to protect the baby. However, that has its disadvantages because pregnant women are more likely to develop diseases, such as the H1N1 influenza, as mentioned in the article. Not only that, women can also contract acute respiratory syndrome, Ebola virus and even the Zika virus, which can also be harmful to the fetus (1). A recent study stated that, not only does Zika virus cause neurological damages in adults, but also malformations and newborn microcephaly in pregnant women (2). It is evident that these different infectious diseases can be very harmful, especially in pregnant women and it is important to be cautious and protected for both the mother and baby.

Recently, scientists have linked a specific protein derived from the placenta to the increase susceptibility of the influenza virus in pregnant women. This protein is known as syncytin-1 and it is an immunosuppressive endogenous retroviral protein (1). When peripheral monocytes (PBMCs) are exposed to this protein it results to an impaired response to the H1N1 virus. The study tested on healthy non-pregnant women and pregnant women and introduced PBMCs to both groups but only the pregnant woman had syncytin-1. Flow cytometry was used to identify and measure releasing cytokines. The results showed that in the presence of syncytin-1, PMBCs had a reduction in the production of certain cytokines such as IFN-α and IFN-λ (1). The reduction of these cytokines causes an enhanced production of IL-10 which would overall impair the adaptive immune response (1). It was also found that there are more immature monocytes in pregnant woman and there is less expression of CD80, CD86, and HLA-DR molecules which plays a key role in fighting off the influenza virus. Is this protein necessary for fetal survival and is it possible to create a drug to inhibit this protein in pregnant women?

The fact that pregnant women are SEVEN times more likely to be hospitalized and twice as likely to die from influenza is frightening, to say the least. It is well known that pregnant women are more susceptible to pathogens due to their suppressed immune system, but I was not aware of just how large of an impact it had on immune response times. It is crucial that women take the necessary precautions by getting vaccinated for not only influenza but for other common diseases as well. A more recent example of a disease that is known to cause ill effects during pregnancy, in particular, is the infamous Zika virus. Women that traveled to locations where vectors for the virus were present such as Brazil were likely to have been exposed to the infection. While the spread of the virus was primarily through the bite of an infected Aedes mosquito, vertical transmission from the mother to her fetus during pregnancy or delivery is common. The virus can cause microcephaly and other malformations in babies. Unfortunately, there is no known vaccination or cure for this virus. Therefore, pregnant women are recommended to stay away from areas affected by the outbreak (1).

There are many factors play a role in immunosuppression during pregnancy, one of the factor is the Early pregnancy factors (EPF) which is a biological active protein that present in the mother’s serum and have immunomodulatory effect by affecting the activity or production of regulatory T cells. As we known that regulatory T cell is the effector T cell that play a role in controlling the immune reaction. There are many research shows that regulatory T cells play a significant role in embryo implantation. One research shows that the immunosuppress function of CD4+ CD25+ regulatory T cell is enhanced by the EPF during pregnancy. CD4+ CD25+ Treg is a T cell that work in immunosuppression for both self and foreign antigens and during pregnancy it can increase maternal tolerance to the embryo. During the study, they found the EPA can convert CD4+ CD25-T cells to CD4+CD25+ Tregs, which then play a role in immunosuppression (1). Regulatory B cell (Breg) also play a role in immunosuppression during pregnancy. Regulatory B cells are known for control autoimmune disease by controlling the differentiation of dendritic cells and effector T cells but promoting the activation pf Treg. Regulatory B cells thus important during pregnancy because it also the source of anti-inflammatory cytokines IL-10 which act against the pro-inflammatory cytokines. Even at the initial conception stage, inflammation resulting from the recognition of paternal antigens is thwarted by the presence of IL-10 (2). It’s very important to know how those lymphocytes and cytokines works during pregnancy because in the future we may be able to modified those cells function during pregnancy so that we can increase the mother’s immune protection against bacterial or viral infection and also increase the maternal tolerance to the fetus at the same time.

I learned some important information reading this article that I was never aware of. I was aware that pregnant women were encouraged to take certain medications like prenatal tablets but I never knew that their immune system was suppressed with their bodies considering the growth a fetus as a foreign object. However, once I saw the word vaccine, I knew there must have been some real hesitations from the pregnant women. Many mothers are already extremely skeptical of the flu vaccine being given to their children due to circulated false information so I could only imagine how they would respond to the getting the vaccine themselves even while pregnant. That’s why I was really interested to read your attached articles, Lanqiao. I wanted to see myself if there was any variation between the fetuses’ of the vaccinated and non-vaccination women. It surprised me that it was actually more beneficial for the fetuses since they were immune to some of the infectious diseases once born. This article below talks about how scientists have been working on a live attenuated vaccine on pregnant mice for the Zika virus. Since the drastically terrible effect of the Zika virus has been shown on a number of newborn babies to infected mothers, these scientists were working on the effects of the vaccine. The results were positively correlated with having a profound effect on the virulent Zika strain, 10-del ZIKV. However, live vaccinations have been reported to actually cause the disease themselves, though a small chance; more work will be done to improve.

The Flu virus affects pregnant women more than the non-pregnant ones because, their immunity decreases during pregnancy to allow for the fetus carried to survive the rejection that may occur, due to the foreign allogenic tissues deriving from the father. Pregnancy in humans is allogenic meaning that genes come from both parents resulting in a fetus that is different from the mother’s. We have heard of patient taking immunosuppressive drugs in order to prevent an organ rejection, so is the case in pregnancy but in this case the immunosuppression occurs naturally. This article has opened my eyes to the subject concerning repetitive miscarriages and the practical use of this knowledge (allogenic pregnancies and repetitive miscarriages). In other articles read, it seems that immunization using allogenic leukocytes has been used to make the woman’s body or immune system accustomed to the foreign cells of the husband to lower the chances of rejection of the fetus hence increasing the chance for a full-term pregnancy (1).

The information from this research is very concerning to pregnant women. Knowing that they are more susceptible to infection should emphasize the importance of vaccination of pregnant women. One of the new information I acquired was about the immune system being suppressed during pregnancy to protect the growing fetus. I always knew pregnant women were under stress and showed signs of being more tired; it might all be related to their suppressed immune system. This is fascinating to me, as a matter of fact, the entire human body is fascinating to me. Knowing that a pregnant woman’s immune system can be suppressed for approximately nine months, and miraculously make it through is incredible. I’m sure pregnant women do acquire these infections, such as the influenza virus, and this has given me a new-found of respect for pregnant women. They are naturally at risk of developing more infections than nonpregnant women, and once that’s over, comes the painful process of childbirth. I hope these types of research will urge more vaccinations within pregnancy women, that’s the most take-home information from this study.

This article is very eye-opening not only to women that are pregnant and fail to get the influenza vaccine, but more over for those women that do not even know that they are pregnant sometimes until 5 to 6 months during the pregnancy. Knowing the risks of not having this vaccine that has to be administered every trimester during pregnancy, put pregnant women in a much live or death situation not only for them but their babies also because pregnant women are more susceptible to various types of infectious diseases and that is why it is recommended that they get vaccinated regularly for their safety and the baby’s safety. However in this study that was conducted in Laos to observed the effect on influenza vaccination in pregnant women on birth outcomes, 5103 women were enrolled, of which 2172 were vaccinated. Among the 4854 who had a live birth, vaccinated women were statistically significantly less likely than unvaccinated women to have an infant born preterm during the period of high influenza virus circulation and the effect remained after adjusting for covariates. There was no effect of vaccine on SGA or mean birth weight. This result shows an indirect evidence of Influenza vaccine safety during pregnancy. Vaccination may prevent 1 in 5 preterm births that occur during periods of high influenza circulation. (1). So is the vaccine the only way to prevent it? and what about those that don’t know they are pregnant?

This article was informative for me. I wasn’t aware that pregnant women’s immune system is suppressed. The end of the article particularly struck me – it’s abundantly clear how important it is to get the influenza vaccine if you’re pregnant. Going off on that, I decided to investigate whether there are individual programs that help promote vaccination for pregnant more than others. As described in this review article, various studies were examined – randomized controlled trials (RCT), cohort studies, and a prospective intervention study. One moderately well RCT showed that pregnant women who were given a pamphlet about influenza had a higher statistically significant vaccination rate. (1) This illustrates the power of simply educating people. It’s just amazing that we can help mitigate the deleterious effects mentioned in the blog post about health outcomes from influenza through this quick and easy intervention.